The Section on Directed Gene Delivery assesses the ability of viral vectors to efficiently deliver genes to appropriate target cells with the end goal of transferring therapeutic genes to cells of the central nervous system. We, and others have determined that although Adeno-Associated Viral (AAV) vectors preferentially target neuronal cells in the central nervous system (CNS) there remain certain limitations to their employment. Retroviral vectors, such as lentiviral and gammaretroviral vectors, have certain advantages over AAV in their ability to stably integrate into the genome of target cells, the absence of an immune response, and the ability to target specific cells in the CNS. Over the past several years we have developed a systematic series of tools to allow us to construct targeted viral vectors that can be purified and concentrated in a manner that will allow delivery to specific cell types in the rodent brain. Vesicular stomatitis virus (VSV) is the envelope of choice for most cell culture work because it imposes a broad host range unto viral vectors. However VSV envelope proteins are cytotoxic and VSV viral enveloped vector particles are neurotoxic, which limits their application, especially in the brain. The envelope protein of gibbon ape leukemia virus (GALV) and a new retrovirus isolated from koalas (Xu W, et al. (2013) PNAS 110:11547-11552) are highly related but employ distinct ubiquitously expressed receptors to infect human cells. GALV uses the ubiquitously expressed inorganic phosphate transporter and KoRV-B the thiamine transporter for entry into cells. Vectors bearing GALV or KoRV-B in contrast to VSV enveloped particles are not cytotoxic. The ability of two highly related envelope proteins to bind distinct receptor offers us an opportunity to map the residues specific to each envelope that confer receptor specificity and provide us with a template for making enveloped vectors that target receptor expressed on specific cells in the CNS. We are constructing human cell lines that produce GALV and KoRV-B enveloped vectors. These cell lines offer distinct advantages over previous vector producing cell lines in that they capable of being continuously modified using enzyme based recombination or gene editing to change the types of viral particles they produce. &#8232;The pace of gene delivery to the brain in a clinical setting has been significantly limited by the lack of translation of advances in vector development. Simply put, CNS payloads have evolved but their delivery systems have not. The availability of optimized preclinical vectors for in vivo testing would be a valuable resource for the national neuroscience community where they would serve seamlessly as tools for hypothesis-driven basic research, and again for clinical research, without needing to be re-discovered and re-presented for the clinic by translational scientists. A repository of such vectors would significantly reduce the time from inception of proof-of-concept design to in vivo execution and would serve to reduce redundancy in the evaluation of vectors through highly interactive collaborations among investigators in neuroscience, molecular virology, and surgical neurology.